Increasing evidence over recent years supports potential roles for subacute inflammation in the pathogenesis of cardiovascular disease as well as insulin resistance and type 2 diabetes. These diseases are themselves linked in terms of predisposition, suggesting that inflammation may form the basis of a pathogenic "common soil." Our lab recently identified the inflammatory IKKbetaNF-kappaB pathway as an underlying feature of insulin resistance. We have found that (A) NF-kappaB is activated by obesity and Western diet in fat and liver, but not muscle, (B) this leads to the production of proinflammatory cytokines (e.g. IL-6, resistin, IL-1beta, TNF-alpha) and other markers and potential mediators of inflammation associated with the metabolic syndrome (e.g. CRP, PAI-1, etc.), (C) transgenic activation of NF-kappaB in fat or liver mimics these events and causes systemic insulin resistance, (D) insulin resistance is transmissible by transplanting affected fat, (E) insulin resistance is reversible by neutralizing cytokines stimulated by NF-kappaB in fat or liver, and (F), perhaps most importantly, inhibition of IKKbeta and NF-kappaB, either genetically or pharmacologically, reverses insulin resistance in animals and humans. This application proposes to test whether obesity- or Western diet-activated NF-kappaB similarly promotes vascular remodeling (i.e. whether this represents the "common soil"). Specifically asked questions include: (1) Does subacute "inflammation" in fat or liver, at levels induced by obesity or Western diet, promote vascular remodeling? Transgenic FIKK and LIKK mice, crossed with atherosclerosis-prone Ldlr-/- and/or Apoe-/- mice, will be fed atherogenic diets and vascular lesions will be scored. (2) Does inhibition of NF-kappaB and consequent inflammation cascades in fat or liver protect mice from developing atherosclerosis? Transgenic FISR and LISR mice crossed with Ldlr-/- and/or Apoe-/- mice will test these questions. (3) A20, a target of NF-kappaB and modulator of its activity, is upregulated by Western diet and obesity. Moreover, a polymorphism in A20 confers genetic susceptibility to atherosclerosis in mice. We will determine whether altered A20 activity influences insulin resistance and vascular remodeling using knock-out and transgenic mouse technologies. (4) Does pharmacologic inhibition of NF-kappaB decrease risk for atherosclerosis? We have used salicylates extensively to inhibit NF-kappaB, reverse insulin resistance and treat diabetes in animals and humans. We now ask whether similar regimens decrease risk for the formation of vascular lesions. These studies test whether shared 'inflammatory' antecedents predispose to the development of both insulin resistance and atherosclerosis, i.e. whether obesity and dietary activation of NF-kappaB in fat and liver represent elements of the long sought "common soil."